Chiral catalysts for asymmetric acylation and related transformations

ABSTRACT

A chiral catalyst comprising a 3,4-disubstituted pyridine, or a salt, N functionalized derivative, dimer or oligomer thereof, wherein the 3-substituent is substantially hindered from rotation about the bond (sp 2 -sp 2  biaryl axis) linking it to pyridine and the 4-substituent is an aliphatic or aromatic amine linked by a single bond to the pyridine, the pyridine nitrogen being functionalized or unfunctionalized, preferably comprising a compound of formula I  
                 
 
     wherein Z is a group substantially hindered from rotation about its bond; and  
     each of R 1  and R 2  are independently selected from C 1-30  alkyl, C 3-30  cyclo alkyl and/or C 3-30  aryl, or NR 1  R 2  form a cyclic amine; wherein R 1  and/or R 2  may be optionally substituted and/or include one or more heteroatoms; a composition or support comprising the catalyst; process for the preparation and resolution thereof; process for stereoselective reaction of an optically inactive substrate using the catalyst; and the optically active reaction product thereof.

[0001] The present invention relates to a class of novel chiralcompounds, a process for the preparation thereof, the use thereof ascatalysts, and a process for mediating asymmetric organictransformations therewith. More specifically, the invention relates to anovel class of atropisomeric analogues of 4-aminopyridine, thepreparation thereof, the use thereof as catalysts, and a method forperforming enantioselective acylation (and related transformations)using the catalyst to preferentially mediate reaction of one enantiomerof an enantiomer pair in a racemic mixture by means of simple-(e.g. H.B. Kagan et al. Top. Stereochem. 1988, 18, 249), parallel-(e.g. E.Vedejs et al. J. Am. Chem. Soc. 1997, 119, 2584), or dynamic-(e.g. S.Caddick et al. Chem. Soc. Rev. 1996, 25, 447) kinetic resolution; orpreferentially mediate reaction of one of two enantiotopic functionalgroups in an achiral meso compound by means of enantioselectivedesymmetrisation (e.g. M. C. Willis, J. Chem. Soc., Perkin Trans. 11999, 1765).

[0002] Kinetic resolution relies on the fact that one enantiomer of anenantiomer pair in a racemic mixture will react at a faster rate with anenantiomerically enriched chiral reagent or in the presence of anenantiomerically enriched chiral catalyst than the other.Enantioselective desymmetrisation relies on the fact that one of twoenantiotopic functional groups in an achiral meso compound will react ata faster rate with an enantiomerically enriched chiral reagent or in thepresence of an enantiomerically enriched chiral catalyst than the other.

[0003] Enantiomerically enriched reagents and catalysts have enormouspotential for the efficient synthesis of enantiomerically highlyenriched products such as pharmaceuticals, agrochemicals, fragrances andflavourings, conducting and light emitting polymers and the like. Theuse of such products in enantiomerically highly enriched form, andpreferably as single enantiomers, is significant both for performancereasons and also in some cases to comply with regulatory constraints.Such constraints apply particularly to compounds intended for human oranimal consumption or application wherein the desired enantiomer isactive and its antipode may be either inert or harmful.

[0004] Enantioselective acylation by means of kinetic resolution orenantioselective desymmetrisation is traditionally performed usingenzymes. High selectivities (E: 7-1000, wherein E is enzymaticenantioselectivity) have been obtained for selected substrates withspecific enzymes (e.g. S. M. Roberts J. Chem. Soc., Perkin Trans. 11998, 157). However, those enzymes which are compatible with the widestrange of substrates (e.g. lipases) are often of low selectivity.Moreover, lipase-mediated acylations can be reversible and undesiredequilibria can cause problems. Additionally, enzymes are provided bynature in only one enantiomeric form and are invariably both thermallyand mechanically unstable. Furthermore their reactions are usuallyheterogeneous, only operate efficiently within narrow reactionparameters, are prone to inhibition phenomena, display poorbatch-to-batch reproducibility, and consequently are difficult toscale-up.

[0005] Recently, chemical methods for mediating enantioselectiveacylation by means of kinetic resolution or enantioselectivedesymmetrisation have begun to emerge. Early methods relied on the useof enantiomerically enriched chiral acylating reagents (e.g. D. A. Evanset al. Tetrahedron Lett. 1993, 34, 5563) but promising chiral chemicalcatalysts are now being developed. Chiral chemical catalysts offer someattractive features relative to the use of enzymes. Reactions catalysedin this manner can be rendered irreversible such that no undesiredequilibria are present. Chemical catalysts can be made in bothenantiomeric forms. Chemical catalysts can be thermally and physicallyrobust. Chemical catalysts can be used under homogeneous conditions.Ideally, they can constitute a tiny fraction of the material to beprocessed, and can be readily recovered.

[0006] The stereoselectivity factor s is the counterpart to enzymaticenantioselectivity, E. Kagan's equation for s for the kinetic resolutionof a given substrate (e.g. a secondary alcohol) reacting by pseudo-firstorder kinetics is given by:${{pr}\quad o\quad d\quad u\quad c\quad {t:s}} = \frac{\ln \left\lbrack {1 - {C\left( {1 + {e\quad e^{\prime}}} \right)}} \right\rbrack}{\ln \left\lbrack {1 - {C\left( {1 - {e\quad e^{\prime}}} \right)}} \right\rbrack}$${r\quad e\quad c\quad o\quad v\quad e\quad r\quad e\quad d\quad s\quad t\quad a\quad r\quad t\quad {in}\quad g\quad m\quad a\quad t\quad e\quad r\quad i\quad a\quad {l:s}} = \frac{\ln \left\lbrack {\left( {1 - C} \right)\left( {1 - {e\quad e}} \right)} \right\rbrack}{\ln \left\lbrack {\left( {1 - C} \right)\left( {1 + {e\quad e}} \right)} \right\rbrack}$

[0007] where C is the conversion (as a fraction of unity, sum of bothreaction enantiomers) while ee and ee′ are the enantiomeric excessvalues of unreacted alcohol and the product, respectively. Theenantiomeric excess ee is also referred to as the optical purity; cc isthe proportion of (major enantiomer)-(minor enantiomer). For example, a90% optical purity is 90% ee, i.e., the enantiomer ratio is 95:5,major:minor. Using as an example acylation of a secondary alcohol viakinetic resolution, if s=50, the ee′ value of the chiral ester productof kinetic resolution remains above 90% until the conversion exceeds46%. For example, the unreacted (chiral) alcohol reaches 80% ee at 50%conversion (C=0.5) and 99% ee at 55% conversion. Theoretically, the lessreactive alcohol enintiomer could therefore be recovered with 90%efficiency and 99% ee (45% yield based on racemic alcohol).

[0008] Impressive selectivities (s: 7-400) have been reported for anumber of enantioselective acylation processes by means of kineticresolution or enantioselective desymmetrisation using a variety ofchiral chemical catalysts. Such chiral chemical catalysts are chiralLewis acids (e.g. F. Iwasaki Org. Letts. 1999, 1, 969), chiralphosphines (e.g. E. Vedejs et al. J. Am. Chem. Soc. 1999, 121, 5813),chiral diamines (e.g. T. Oriyama et al. Chem. Lett. 1999, 265), chiralimidazoles (e.g. S. J. Miller et al. J. Org. Chem. 1998, 0, 6784), andchiral 4-aminopyridines (e.g. E. Vedejs et al. J. Am. Chem. Soc. 1997,119, 2584; G. C. Fu et al. J. Am. Chem. Soc. 1999, 121, 5091; G. C. Fuet al. J. Org. Chem. 1998, 63, 2794; K. Fuji et al. J. Am. Chem. Soc.1997, 119, 3169). All these chiral chemical catalysts except the chiralLewis acids are believed to operate by nucleophilic catalysis. Apossible mechanism of nucleophilic catalysis of acylation of a secondaryalcohol mediated by the achiral 4-aminopyridine derivative4-dimethylaminopyridine (DMAP) is illustrated in Scheme A.

[0009] Of the chiral 4-aminopyridine-based catalysts, Fu's planar chiralferrocenyl chiral 4-aminopyrindine has been shown to be the mostversatile (e.g. G. C. Fu et al. J. Org. Chem. 1998, 63, 2794). Itcatalyses a variety of useful enantioselective acylation processes bymeans of kinetic resolution (e.g. of arylalkylcarbinols with aceticanhydride) via nucleophilic catalysis with excellent selectivity (s:7-100). However, the published synthesis involves 13 linear steps, hasan overall yield of 0.6% from adiponitrile (for the racemate), requiresglove-box techniques, and involves chiral stationary phasehigh-performance liquid chromatography (HPLC) for the final enantiomerseparation. Additionally, it is a slow catalyst, typically requiringseveral days at 0° C. in tert-amyl alcohol to give efficient resolution.

[0010] Accordingly, there is a need for enantioselective catalysts whichare capable of mediating enantioselective acylation with highselectivity, which can be readily synthesised in high yield and used inlow quantities, and which are readily recovered.

[0011] We have now found a novel class of catalysts that meet some orall of these needs, specifically provide comparable selectivity, arefaster catalysts and are readily prepared, and moreover provide a numberof additional advantages. Specifically we have developed a conceptuallynew class of nucleophilic chiral 4-aminopyridine molecules as catalysts.These molecules possess axial asymmetry as the result of restrictedrotation about a highly hindered sp²-sp² biaryl axis.

[0012] In the broadest aspect of the invention there is provided achiral catalyst comprising a 3,4-disubstituted pyridine, or a salt,N-functionalised derivative, dimer or oligomer thereof, wherein the3-substituent is substantially hindered from rotation about the bond(sp²-sp² biaryl axis) linking it to pyridine and the 4-substituent is analiphatic or aromatic amine linked by a single bond to the pyridine, thepyridine nitrogen being functionalised or unfunctionalised. The catalystmay be provided as its racemic mixture or as only one of itsatropisomers.

[0013] It is a particular advantage of the invention that the compoundsare readily synthesised and resolved. The catalyst is highly active andcatalyses rapid reaction.

[0014] We have found that with appropriate substitution the atropisomersof the pyridine derivatives of the invention are highly resistant torotation about the bond at the 3-position, rendering the atropisomershighly resistant to racemisation.

[0015] Accordingly, in a first aspect of the invention there is provideda catalyst comprising a compound of formula I:

[0016] wherein Z is a group substantially hindered from rotation aboutits bond; and

[0017] each of R¹ and R² are independently selected from C₁₋₃₀ alkyl,C₃₋₃₀ cyclo alkyl and/or C₃₋₃₀ aryl, or NR¹ R² form a cyclic amine;wherein R¹ and/or R² may be optionally substituted and/or include one ormore heteroatoms; or

[0018] a salt, N-functionalised derivative, dimer or oligomer thereof.

[0019] Preferably the pyridine 5-substituent is hydrogen.

[0020] A class of 4,5-(fused) substituted compounds is disclosed in A.C. Spivey et al. Tetrahedron Lett. 1998, 3, 8919, which studied rates ofcatalysis. We have now however found that 5-position substitution isdetrimental to the efficiency of compounds as asymmetric catalysts, incontrast to the class of compounds of the invention.

[0021] More preferably the invention relates to a catalyst comprising acompund of formula II:

[0022] wherein R¹ and R² are as hereinbefore defined;

[0023] R³ is selected from C₁₋₂₀ alkyl, C₃₋₂₀ cyclo alkyl and/or C₃₋₂₀aryl, wherein R³ may be optionally substituted and/or include one ormore hetero atoms; and

[0024] R⁴ is C₁₋₂₀ alkyl, C₃₋₂₀ cyclo alkyl and/or C₃₋₂₀ aryl or R⁴ andR⁵ together are a C₃₋₂₀ fused cyclic or aromatic group wherein R⁴ or R⁴and R⁵ together may be optionally substituted or include one or morehetero atoms; or

[0025] a salt, N-functionalised derivative, dimer or oligomer thereof.

[0026] The compounds of formulae I or II as hereinbefore defined may befurther substituted or unsubstituted in the pyridine 2- and/or6-positions and/or in the Z ring. Substituents are independentlyselected from one or more R⁶, wherein R⁶ is selected from for exampleC₁₋₂₀ alkyl or C₃₋₂₀ aryl, either being optionally substituted orincluding one or more heteroatoms.

[0027] Preferably each of R¹ and R² and R³ independently are selectedfrom: straight or branched chain lower (C₁₋₅) or higher (C₆₋₂₀) alkyl,more preferably methyl, ethyl, propyl, butyl, pentyl or hexyl, heptyl,octyl; or from C₃₋₂₀ cyclo alkyl, preferably C₃-C₁₄ cyclo alkyl; or fromC₆₋₂₄ aryl, more preferably an unfused, optionally Spiro 1, 2, 3, 4 or 5ring alkyl or aryl structure; any of which are optionally substitutedand/or include at least one heteroatom; or

[0028] R¹ and R² together form an optionally substituted cyclo amine,such as

[0029] wherein m=1-8 and each Y is independently selected from(CH₂)_(n)Y′_(p)

[0030] wherein n=1-8, p=0-4 and the sum of n and p is at least 2, andeach Y′ is independently selected from NR⁷, O, S, P or Si,

[0031] preferably Y is (CH₂)_(n′)Y′ wherein n′ is 1-3 or the cyclicamine is

[0032] wherein R⁷ is as hereinbefore defined for R¹ or forms a dimer oroligomer of a moiety of compound of formula I:

[0033] or R³ comprises optionally substituted phenyl or biphenyl, suchas optionally substituted (3,5-diphenyl)phenyl, such as[(3′,3″,5′,5″-tetramethyl)-3,5-diphenyl]phenyl.

[0034] Preferably the catalyst as hereinbefore defined is a compound offormula III:

[0035] wherein R¹-R³ and R⁶ are as hereinbefore defined; or a salt,N-functionalised derivative, dimer or oligomer thereof.

[0036] Any optional substituents or R⁶ as hereinbefore defined may beindependently selected from any groups that improve or do not detractfrom performance of the compounds as catalyst.

[0037] Suitable substituents include halide, hydroxy, amino, alkoxy,alkyl, cycloalkyl aryl, such as hereinbefore preferably defined for R¹,R² or R³.

[0038] Heteroatoms as hereinbefore defined include optionallysubstituted N, O, S, P, Si.

[0039] More preferably, the catalyst as hereinbefore defined is acompound of formula III in which: R¹ and R² are methyl, ethyl, propyl,or butyl; or R¹ and R² together form a pyrrolidinyl-, piperidinyl-, ormorpholinyl ring; and R³ comprises a phenyl, 4′-biphenyl,(3,5-diphenyl)phenyl, or [(3′,3″,5′,5″-tetramethyl)-3,5-diphenyl]phenyl.

[0040] Without being limited to this theory it is thought that thecompounds of the invention may be rationally designed with respect tothe atropisomeric moiety by selection of the group preventing rotationabout the pyridine 3-bond, the active catalytic moiety by selection ofthe amine substituents, and the transformation selective moiety byvariation at the pyridine N. Without varying the pyridine N the catalystis effective for acylation reactions and other transformations for whichthe high nucleophilicity of this moiety elicits catalytic behaviourwhilst the formation of various salts and N-dipolar adducts, for exampleN-oxide and N-borane adducts, will affect the reactive nature of the Nand provide access to other transformations.

[0041] In a further aspect of the invention there is provided acomposition or a support comprising a catalytically effective amount ofa catalyst as hereinbefore defined together with suitable solvent,dilutent and the like or together with a suitable linker on amacromolecule, polymer or a solid support. A supported catalyst may beuseful in combinatorial chemistry for conducting plural parallelreaction with labelling and identification of reaction products therebynegating the need for analysis.

[0042] In a further aspect of the invention there is provided a compoundor formula I, II or III as hereinbefore defined.

[0043] In a further aspect of the invention there is provided a processfor the preparation of a compound of formula I, TI or III ashereinbefore defined comprising cross-coupling a compound of formula IVwith an organometal derivative R³-M (Scheme B).

[0044] Wherein each R⁶ independently is hydrogen or is defined ashereinabove, and R¹,R²,R³,R⁴, and R⁵ are defined as hereinabove andwherein X is a group which is such that palladium or nickel or a similartransition metal can be oxidatively inserted into the bond between X andthe adjacent aryl carbon atom. M is Li, Mg, Zn, Hg, Ti, Al, Zr, TI, Sn,B and mixtures thereof or a derivative, salt or “ate” complex thereof.

[0045] Preferably, X is a halide, sulfonate, for example trifloxy (OTf),or diazonium salt.

[0046] Preferably, the cross-coupling is catalysed by palladium(0) ornickel(0). Preferably, M=MgX, SnR₃, or B(OR)₂ (i.e. the Kharasch,Stille, and Suzuki cross-coupling protocols respectively, e.g. S. P.Stanforth, Tetrahedron 1998, 64, 263).

[0047] For example, intermediate IV wherein X=OTf is cross-coupled withan appropriate organo-Grignard derivative (R³-MgBr) in the presence of acatalytic quantity of palladium(0) in a Kharasch-type process.

[0048] The product is obtained as a racemic mixture and may subsequentlybe separated by methods as known in the art, such as by chiralstationary phase HPLC as previously disclosed (A. C. Spivey et al.Tetrahedron Lett. 1998, 39, 8919), or preferably byatropisomer-selective transformation with salt formation, enablingresolution. Preferably suitable salt-forming agents are identified byparallel screening as disclosed in “Application of Automation andThermal Analysis to Resolving Agent Selection”, M. B. Mitchell et al.Org. Proc. Res. Dev. 1999, 3, 161, using suitable selection of chiralacids in solution of solvents such as ethanol or less polar solventssuch as ethyl acetate.

[0049] More preferably separation is by atropisomer-selective saltformation using a commercially available chiral acid:(S)-N-tert-butoxycarbonyl-O-benzyl-tyrosine in isopropanol.

[0050] Alternatively, the product may be obtained directly from thecross-coupling reaction as a non-racemic mixture by incorporating chiralligands in the coupling procedure (cƒ. S. L. Buchwald et al. J. Am Chem.Soc. 2000, ASAP web release date 11th November), preferably binapthylligands.

[0051] In a further aspect of the invention there is provided a processfor the preparation of an intermediate of formula IV as hereinbeforedefined comprising: cross-coupling with concomitant hydrodehalogenation,of an intermediate 4-aminopyridine derivative of formula VI to anarylmetal V; and, for compounds wherein X≠Y, subsequent conversion ofgroup Y into group X by methods known in the art (Scheme C).

[0052] Wherein R¹ and R², and R⁴, R⁵, and R⁶ and M are as hereinbeforedefined, W is a halide substituent, and Y is as hitherto defined for Xor a substituent of the form OR wherein R is a substituent, known in theart as a protecting group, which allows for conversion to thecorresponding compound wherein Y=X by methods known in the art to thecorresponding compound wherein Y═OH which is readily converted bymethods known in the art to a substituent hitherto defined as X.

[0053] Preferably, W is a bromide and Y is a substituent of the form ORwherein R is a protecting group which allows for conversion byhydrogenolysis, as known in the art, to the corresponding phenol whereinY═OH [e.g. benzyloxy (OBn), or substituted benzyloxy] and transformationof this phenol to an aryl sulfonate (e.g. triflate) suitable forcross-coupling is by methods known in the art (e.g. by reaction with anappropriate sulfonic anhydride, -fluoride or -chloride).

[0054] Preferably, the cross-coupling is catalysed by palladium(0).Preferably, M═B(OR)₂ (i.e. a Suzuki cross-coupling protocol, e.g. N.Miyaura et al. Synth. Commun. 1981, 11, 513) which, under appropriateconditions as known in the art, also effects hydrodehalogenation of the5-halogen substituent.

[0055] For example, intermediate VI wherein W═Br and R¹═R²═Et iscross-coupled with an appropriate boronic acid derivative V whereinY═OBn, and M═B(OH)₂ in the presence of a catalytic quantity ofpalladiiim(0) in a Suzuki-type process with concomitant5-hydrodebromination to give, after transformation of Y═OBn to Y═OTf byknown methods, intermediate IV.

[0056] Utilisation of cross-coupling of 3-halogen-substituted DMAPderivatives with appropriate organo-metal derivatives by analogy to amethod previously disclosed (A. C. Spivey et al. Tetrahedron Lett. 1998,38, 8919) can be used to access compounds of structure IV (A. C. Spiveyet al. J Org. Chem. 2000, 65, 3154) but this normally high-yieldingprocess gave very poor yields for the class of analogues of theinvention (Scheme D).

[0057] Notwithstanding the possibility that this type of cross-couplingcould be optimised, we developed the novel process outlined hithertofore(Scheme C).

[0058] The compounds are obtained in excellent yield. The process isalso suited for preparation of a range of analogues having differentsubstituents, specifically amine and 3-pyridyl substituents.

[0059] The aryl boronate coupling partner V can be obtained commerciallyor by known means from the appropriate aryl halide, for example as shownin Scheme E, by conversion from commercially available1-bromo-2-naphthol or an analogue thereof (A. C. Spivey et al. J Org.Chem. 2000, 65, 3154).

[0060] The intermediate 4-aminopyridine derivative of formula VI can beobtained according to the process outlined in Scheme F.

[0061] Herein, intermediate 4-aminopyridine derivative of formula VI isobtained from reaction of the trihalopryidine VII with the appropriatesecondary amine in the corresponding formamide solvent at elevatedtemperature. The intermediate trihalopyridine of formula VII is suitablyobtained by reaction of the corresponding 3,5-dihalo-4-pyridone offormula VIII with a chlorinating agent. The 3,5-dihalo-4-pyridone offormula VIII is suitably obtained by halogenation of commerciallyavailable 4-pyridone.

[0062] It is a particular advantage of the invention that the compoundsmay be prepared simply and conveniently in high yield and convenientlyseparated into atropisomers illustrated in Scheme G.

[0063] Kinetic parameters were obtained and indicated that anenantiomerically pure sample of suitably highly substituted compounds ofthe invention would lose much less than 1% of their optical purity overone year in solution at room temperature (A. C. Spivey et al. J. Org.Chem. 2000, 65, 3154).

[0064] In a further aspect of the invention there is provided a novelintermediate as hereinbefore defined.

[0065] In a further aspect of the invention there is provided a catalystcomprising an enantiomer of a compound or formula I, II, or III ashereinbefore defined.

[0066] The catalyst is highly active and catalyses rapid reaction.

[0067] In a further aspect of the invention there is provided a processfor stereoselective reaction of a catalyst of formula I, II, III ashereinbefore defined with an optically inactive substrate to provide oneor both enantiomers of a derivative thereof, with simultaneous orsubsequent recovery of the catalyst. The invention includes subsequentseparation of the product enantiomers.

[0068] The reaction may be any suitable reaction that may be catalysedby the catalyst of the invention, including its salts and N-dipolaradducts.

[0069] Preferably the process comprises the enantioselective acylationby means of kinetic resolution of e.g. a secondary or tertiary alcoholor primary or secondary amine for which the acylated or furtherderivative can be industrially useful in enantiomeric form as apharmaceutical, agrochemical, fragrance, flavouring or as a constituentof a high-value electrically or optically active polymer or the like.

[0070] More preferably, the process comprises the reaction of an alcoholof formula IX, wherein R⁸ and R⁹ are independently selected from C₁ _(⁻)₅₀ alkyl, C₃₋₅₀ cyclo alkyl or C₃₋₃₀ aryl, with an acylating agentR¹⁰COU, wherein R¹⁰ is optionally substituted C₁ _(⁻) ₁₅ alkyl or C₁_(⁻) ₁₂ aryl and U is an appropriate leaving group, such as anhydride,under acylating conditions, as known in the art, in the presence of aenantiomerically highly enriched catalyst (preferably >90% ee) offormula I, II or III as hereinbefore defined, according to Scheme H.

[0071] Preferably, the catalyst is enantiomerically enriched such thatits ee is ≧98%. More preferably, the catalyst is enantiomericallyenriched such that its ee is ≧99%, more preferably ≧99.9%.

[0072] Suitable choice of acylating agent, temperature, solvent, andstoichiometric base have been found to improve selectivity of reaction.

[0073] The transformation is catalysed with high selectivity (s: 7-500).Selectivities in excess of 50 may be obtained by optimisation. Theenantiomeric excess of the products (ee′) may be improved, as known inthe art, by repeat transformation using the opposite enantiomer ofcatalyst (i.e. double kinetic resolution: e.g. S. M. Brown et al.Tetrahedron: Asymmetry 1991, 2, 511).

[0074] Resolution of enantiomers in the process of the inventionprovides optical purity in excess of 70% preferably in excess of 90%depending on the extent of conversion C.

[0075] Alternatively, the process comprises the enantioselectiveacylation by means of enantioselective desymmetrisation of an achiralmeso diol or diamine. The enantioselective reaction of enantiotopicfunctional groups under acylating conditions in these situations canyield a single enantiomer of the product in yields up to 100%.Additionally, as known in the art, it is usual in such systems that theenantiomeric purity of the monofunctionalised product increases as afunction of conversion due to preferential further conversion (i.e.kinetic resolution) of the minor enantiomer into a meso difunctionalisedproduct (i.e. the ‘meso-trick’: e.g. S. L. Schreiber, et al. J. Am.Chem. Soc. 1987, 109, 1525).

[0076] Catalyst recovery is suitably 90-100%. Advantageously, catalyticperformance is highly reproducible.

[0077] The catalyst of the invention may be used in any suitable formand amount. Catalytic amounts of 0.001 to 2 mol %, preferably 0.01 to0.2 mol %, more preferably 0.05 to 0.15 mol % may be used.

[0078] In a further aspect of the invention there is provided a productof a catalytic reaction obtained with use of a catalyst as hereinbeforedefined.

[0079] The invention is now illustrated in non-limiting manner withreference to the following examples and figures.

EXAMPLE 1 Preparation of a Compound of Formula III

[0080] 3,5-Dibromo-4-pyridone (VIII, W═Br)

[0081] The dibromination of 4-pyridone was carried out according to amodified known method (O. S. Tee et al. Can. J. Chem. 1983, 61, 2556).Thus, to an ice-cooled and mechanically stirred solution of 4-pyridone(34.9 g, 0.367 mol) and KOH (41.2 g, 0.736 mol) in water (700 mL) wasadded Br₂ (37.9 mL, 0.735 mol) dropwise over 30 min. After additional 30min, the white precipitate was filtered off, washed with a copiousamount of water, and dried in vacuo to give the crude3,5-dibromo-4-pyridone (VIII, W═Br) (79.0 g, 85%) which was used in thenext step without further purification.

[0082] 3,5-Dibromo-4-chloropyridine (VII, W═Br)

[0083] A mixture of 3,5-dibromo-4-pyridone (VIII, W═Br) (79.0 g, 0.312mol) and PCl₅ (79 g, 0.38 mol) was kept at 160° C. for 3 h. The reactionmixture was cooled to 0° C. and quenched by slow addition of water (200mL). The resulting precipitate was crushed, filtered off, washed withwater, and transferred on top of a flash silica column which wassubsequently eluted with CH₂Cl₂. The crude product thus obtained wascrystallised from EtOH to give the title compound,3,5-dibromo-4-chloropyridine (VII, W=Br) (73.9 g, 72%) as white needles:R_(ƒ)=0.60 (CH₂Cl₂); mp 95.0-96.5° C. (EtOH); ¹H NMR (250 MHz, CDCl₃)δ8.65 (s); ¹³C NMR (63 MHz, CDCl₃) δ121.8, 144.0, and 150.9; IR (CHCl₃)ν_(max) 1549, 1524, 1410, and 1394 cm⁻¹; MS (EI⁺) m/z (rel intensity)271 (100%, M⁺) and 192 (30); HRMS calcd for C₅H₂Br₂CIN (M⁺) 268.8242,found 268.8231.

[0084]3,5-Dibromo-4-(diethylamino)pyridine (VI, R¹═R²═Et, W═Br)

[0085] A mixture of trihalopyridine VII (W═Br) (18.8 g, 70.0 mmol),Et₂NH (21.7 mL, 0.210 mol), and N,N-diethylformamide (35 mL) was kept ina sealed high-pressure tube at 170° C. for 20 h. The reaction mixturewas cooled to room temperature, dissolved in EtOAc (300 mL), and washedwith 1M K₂CO₃ (200 mL) and water (8×200 mL). The organic layer was driedwith MgSO₄ and evaporated in vacuo to give a brown oil. Purification byflash chromatography (CH₂Cl₂) gave the title compound,3,5-dibromo-4-(diethylamino)pyridine (VI, R¹═R²═Et, W═Br), (20.3 g, 94%)as a yellow oil: R_(ƒ)=0.45 (CH₂Cl₂); ¹H NMR (250 MHz, CDCl₃) δ1.01 (t,J=7.0 Hz, 6H), 3.26 (q, J=7.0 Hz, 4H), and 8.49 (s, 2H); ¹³C NMR (63MHz, CDCl₃) δ14.10, 46.05, 122.9, 151.9, and 154.1; IR (CHCl₃) ν_(max)2976, 1553, 1457, 1167 cm⁻¹; MS (EI⁺) m/z (rel intensity) 308 (15%, M⁺),193 (100), and 264 (30); HRMS calcd for C₉H₁₂Br₂N₂ (M⁺) 305.9367, found305.9366.

[0086] 1-Bromo-2-(phenylmethoxy)naphthalene

[0087] To a suspension of 1-bromo-2-naphthol (15.0 g, 67.3 mmol) andK₂CO3 (18.6 g, 135 mmol) in DMF (100 mL) was added benzyl bromide (9.6mL, 81 mmol) and the mixture was stirred at 60° C. for 5 h. Aftercooling to room temperature, the solvent was evaporated in vacuo and theresidue, dissolved in a small amount of CH₂Cl₂, passed through a thinpad of flash silica. Fractions containing the product were evaporated invacuo to give an off-white solid. Crystallisation from CH₂Cl₂/petrolgave the title compound, 1-bromo-2-(phenylmethoxy)naphthalene, as awhite crystalline solid (16.0 g, 76%). The mother liquor wasconcentrated and purified by flash chromatography (petrol/CH₂Cl₂, 2/1)to give an additional amount of the product (3.7 g, 17%; total yield:93%). R_(ƒ)=0.50 (petrol/CH₂Cl₂, 2/1); mp 104-106° C. (CH₂Cl₂/petrol);¹H NMR (250 MHz, CDCl₃) a 5.35 (s, 2H), 7.32 (d, J=9.0 Hz, 1H),7.38-7.50 (m, 4H), 7.57-7.66 (m, 2H), 7.79-7.86 (m, 3H), and 8.31 (d,J=8.5 Hz, 1H); ¹³CNMR (63 MHz, CDCl₃) δ71.81, 110.0, 115.6, 124.6,126.3, 127.2, 127.8, 128.1 (2C), 128.7, 128.9, 130.1, 133.2, 136.7 and153.0; IR (CHCl₃) ν_(max) 1626, 1596, 1502, 1350, and 1268 cm⁻¹; MS(EI⁺) m/z (rel intensity) 314/312 (25%, M⁺) and 91 (100); HRMS calcd forC₁₇H₁₃BrO (M⁺) 312.0150, found 312.0150. Anal. Calcd for C₁₇H₁₃BrO: C,65.19; H, 4.18; Br, 25.51. Found: C, 64.94; H, 4.12; Br, 25.71.

[0088]2-(Phenylmethoxy)-1-napthaleneboronic acid (V, R⁴-R⁵=fused arylring, R⁶=H)

[0089] To a suspension of 1-bromo-2-(phenylmethoxy)naphthalene (6.26 g,20.0 mmol) in Et₂O (75 mL) at −78° C. was added n-BuLi (8.0 mL, 2.5 M,20 mmol) in hexanes and the mixture was stirred at 0° C. for 1 h. Afterre-cooling to −78° C., the mixture was treated with trimethyl borate(2.5 mL, 22 mmol) and allowed to warm to room temperature overnight. Theresulting mixture was quenched with 1M HCl (50 mL) and stirred at roomtemperature for 45 min. The phases were separated and the extraction wascompleted with CH₂Cl₂. The combined organic extracts were dried (MgSO₄)and evaporated in vacuo to give the title compound,2-(phenylmethoxy)-1-napthaleneboronic acid as a white powder (4.62 g,83%), which was used in the next step without further purification. Foranalytical purposes, a small amount of the product was re-crystallisedfrom MeOH/H₂O: mp 133.0-135.0° C. (MeOH/H₂O); ¹H NMR (250 MHz, d₄-MeOH).δ5.20 (s, 2H), 7.28-7.60 (m, 9H), and 7.56-7.88 (m, 2H); ¹³C NMR (63MHz, d₄-MeOH) δ71.95, 115.4, 124.8, 127.7 (2C), 128.4, 128.9, 129.5,129.6, 130.7 (2C?), 131.8, 137.2, 139.0 and 159.7;^(i) IR (CHCl₃)ν_(max) 3609, 3490, 1592, 1509, 1386, and 1332 cm⁻¹; MS (EI⁺) m/z (relintensity) 278 (10%, M⁺), 234 (10), and 91 (100); HRMS calcd forC₁₇H15BO₃ (M⁺) 277.1151, found 277.1163. Anal. Calcd for C₁₇H₁₅BO₃: C,73.42; H, 5.44. Found: C, 73.07; H, 5.33.

[0090] Diethyl{3-[2-(phenylmethoxy)naphthyl](4-pyridyl)}amine (IV,X═OBn, R¹═R²═Et, R⁴-R⁵=fused aryl ring, R⁶═H)

[0091] To a solution of aryl dibromide VI (R¹═R²═Et, W═Br) (5.13 g, 16.7mmol) in toluene (100 mL) and ethanol (5 mL) was added 2M NaOH (30 mL)followed by Pd(PPh₃)₄ (965 mg, 0.835 mmol) and arylboronic acid V (R⁴-R⁵=fused aryl ring, R⁶═H) (5.56 g, 20.0 mmol). The mixture was refluxedfor 22 h, cooled to room temperature, and diluted with water (100 mL).The phases were separated and the extraction was completed with CH₂Cl₂.The combined organic extracts were dried (MgSO₄) and evaporated in vacuoto give a brown oil. The residue was purified by flash chromatography(CH₂Cl₂→EtOAc) to give the title compound,diethyl{3-[2-(phenylmethoxy)naphthyl](4-pyridyl)}amine (IV, X═OBn,R¹═R²═Et, R⁴-R⁵=fused aryl ring, R⁶═H), (3.77 g, 59%) as a yellow oil:R_(ƒ)=0.25 (EtOAc); ¹H NMR (250 MHz, CDCl₃) δ0.70 (t, J=7.0 Hz, 6H),2.85-3.06 (m, 4H), 5.15 (s, 2H), 6.79 (d, J=6.0 Hz, 1H), 7.20-7.44 (m,9H), 7.75 8.07 (m, 2H), 8.07 (s, 1H), and 8.31 (d, J=6.0 Hz, 1H); ¹³CNMR (63 MHz, CDCl₃) δ12.36, 44.83, 70.86, 111.0, 115.0, 120.3, 123.3,123.9, 125.5, 126.5, 126.8, 127.7, 127.9, 128.4, 129.2, 129.4, 133.2,137.3, 148.6, 153.1, 153.6, and 155.3; IR (CHCl₃) ν_(max) 2979, 1587,1505, and 1271 cm⁻¹; MS (EI⁺) m/z (rel intensity) 382 (15%, M⁺) and 277(100); HRMS calcd for C₂₀H₂₆N₂O (M⁺) 382.2045, found 382.2041.

[0092] 1-[4-(Diethylamino)-3-pyridyl]-2-naphthyl (trifluoromethyl)sulfonate (IV, X═OTf, R¹═R²═Et, R⁴-R⁵=fused aryl ring, R⁶═H)

[0093] A solution of benzyl ether IV (X═OBn, R¹═R²═Et, R⁴-R⁵═fused arylring, R⁶═H) (3.48 g, 9.10 mmol) in EtOH (120 mL) was hydrogenated undernormal pressure in the presence of 10% Pd/C (1.0 g) for 9 h (TLC). Thereaction mixture was filtered through a thin pad of Celite andevaporated in vacuo to give a crude phenol (2.60 g), which was dissolvedin pyridine (30 mL) and treated at 0° C. with Tf₂O (1.70 mL, 10.0 mmol).After 2 h, the solvent was evaporated in vacuo and the residuepartitioned between CH₂Cl₂ and water. The phases were separated and theextraction was completed with additional portions of CH₂Cl₂. Thecombined extracts were dried (MgSO₄) and evaporated in vacuo to give abrown oil. Purification by flash chromatography (CH₂Cl2→EtOAc) gave thetitle compound, 1-[4-(diethylamino)-3-pyridyl]-2-naphthyl(trifluoromethyl)sulfonate (IV, X═OTf, R¹═R²═Et, R⁴-R⁵=fused aryl ring,R⁶═H), (2.94, 76%) as a yellow oil: R_(ƒ)=0.50 (EtOAc); ¹H NMR (250 MHz,CDCl₃) 5 0.77 (t, J=7.0 Hz, 6H), 2.77-3.02 (m, 4H), 6.85 (d, J=6.0 Hz,1H), 7.45-7.59 (m, 3H), 7.77 (d, J=5.5 Hz, 1H), 7.92-7.95 (m, 2H), 8.14(s, 1H), and 8.38 (d, J=6.0 Hz, 1H); ¹³C NMR (63 MHz, CDCl₃) 5 12.19,44.87, 112.1, 117.8, 118.3 (q, J=320 Hz), 119.6, 126.5, 127.2, 127.9,128.4, 129.4, 130.3, 132.7, 132.8, 144.8, 150.1, 153.6, and 155.6; IR(CHCl₃) ν_(max) 2978, 1585, 1500, 1421, and 1142 cm⁻¹.

[0094] (±)-Diethyl[3-(2-phenyinaphthyl)(4-pyridyl)]amine [(±)-III,R¹═R²═Et, R³═Ph, R⁶═H]

[0095] To a solution of triflate IV (X═OTf, R¹═R²═Et, R⁴-R⁵=fused arylring, R⁶═H) (193 mg, 0.45 mmol) in Et₂O (3 mL) was added PdCl₂(dppp) (13mg, 22 μmol) followed by PhMgBr (300 μL, 3.0 M, 0.90 mmol) in Et₂O. Themixture was refluxed for 16 h, cooled to room temperature, quenched withwater (10 mL), and extracted with CH₂Cl₂. The combined extracts weredried (MgSO₄) and evaporated in vacuo to give a brown oil. Purificationby flash chromatography (CH₂Cl₂/EtOAc, 3/1→EtOAc) gave the titlecompound, (±)-diethyl[3-(2-phenylnaphthyl)(4-pyridyl)]amine [(±)-III,R¹═R²═Et, R³═Ph, R⁶═H], (147 mg, 93%) as a white solid: Rf=0.25 (EtOAc);¹H NMR (250 MHz, CDCl₃) δ0.52 (t, J=7.0 Hz, 6H), 2.55-2.88 (m, 4H), 6.50(d, J=6.0 Hz, 1H), 7.09-7.18 (m, 5H), 7.41-7.56 (m, 3H), 7.82-7.94 (m,3H), 8.18 (s, 1H), and 8.22 (d, J=6.0 Hz, 1H); ¹³C NMR (63 MHz, CDCl₃)δ12.07, 44.56, 111.7, 122.9, 126.0, 126.4, 126.6 (2C), 127.6, 128.1(2C), 128.6, 129.6, 132.4, 133.1, 134.0, 138.8, 141.7, 148.7, 154.3, and155.0; IR (CHCl₃) ν_(max) 2976, 1586, and 1496 cm⁻¹.

EXAMPLE A1 Optical Resolution of the Racemic Biaryl [(±)-III, R¹═R²═Et,R³═Ph, R⁶═H].

[0096] The product was resolved according to the following techniques

[0097] Method 1—Chiral HPLC

[0098] The enantiomers of the biaryl III (R¹═R²═Et, R³═Ph, R⁶═H) wereseparated using semi-preparative chiral HPLC (Chiralcel OD column, 1cm×25 cm; hexanes/EtOAc/Et₂NH, 80/19.2/0.8; 4 mL min-1; 30° C.). UVdetection was performed at 250 nm. Injections of ˜7 mg of the racematein 70 μL of CH₂Cl₂ were made every 12 min. Enantiomer (−)-III wascollected from 8.7 to 10.1 min, and the enantiomer (+)-III was collectedfrom 13.3 to 15.9 min. The enantiomer (+)-III was re-purified using thesame column (hexanes/EtOAc/Et₂NH, 75/24/1; 4 mL min-1; 30° C.) with theproduct collected from 11.2 to 13.8 min. The enantiomers were furtherpurified by flash chromatography (EtOAc) to give final products as whitesolids. Analytical chiral HPLC revealed the enantiomeric purityof >99.9% for both the levorotatory {[α]²⁵ _(D)-124 (c 0.58 in CHCl₃)}and the dextrorotatory {[α]²⁵ _(D)+126 (c 0.57 in CHCl₃)} enantiomer.

[0099] Method 2—Salt Formation: I) Resolving Agent Screen:

[0100] Using 480.0 mg (1.362 mmol) of (±)-biaryl III (R¹═R²═Et, R³═Ph,R⁶═H) and 15.2 ml Ethanol a 0.09 M stock solution of the racemate wasprepared.

[0101] Apparatus:

[0102] Using an ACT Chemtech robot, 63×100 μl of this solution was addedto 63 wells of a 96 well plate (well positions shown in table). Thechiral acid solutions listed below were now added (100 μl) to theindicated well positions. The plate was sealed with a sealing strip,each well cover having a pinhole to allow solvent to escape. The platewas placed in a vacuum oven, under vacuum and at 40° C. overnight.Chiral Acid Well Ref No. (R)-(−)-N-(3,5-DINITROBENZOYL)-ALPHA-PHENYL H1101 GLYCINE BOC-O-BENZYL-L-TYROSINE G1 104 N-CBZ-L-TRYPTOPHAN F1 105N-ACETYL-L-TRYPTOPHAN E1 106 N-ACETYLHYDROXY-L-PROLINE D1 108 Z-PHE-OHC1 109 BOC-L-TERT-LEUCINE B1 110 BOC-L-VALINE A1 111 Z-L-SERINE H2 112DANSYL-L-PHENYLALANINE G2 113 BOC-MEPHE-OH F2 114BOC-N-ME-TYR(2,6-DICHLORO-BZL)-PH E2 115 Z-D-PYR-OH D2 117 BOC-TIC-OH C2119 Z-GLU(OTBU)-OH B2 120 (−)-Z-PIPERAZIC ACID A2 121N-ACETYL-L-PHENYTLALANINE H3 122 N-(9-FLUORENYLMETHOXY-CARBONYL)-L- G3123 TRYPTOPHAN (S)-(+)-2-METHYLBUTYRIC ACID F3 201 (S)-3-PHENYLBUTYRICACID E3 202 (S)-3-HYDROXYBUTYRIC ACID D3 203(S)-(+)-ALPHA-HYDROXY-1,3-DIOXO-2- C3 204 ISOINDOLINEBUTYRIC ACID1R-(+)-BAMPHANIC ACID B3 302 D-CAMPHORIC ACID A3 303D-(+)-10-CAMPHORSULFONIC ACID H4 304 D-PYROGLUTAMIC ACID G4 401D-SACCHARIC ACID 1,4-LACTONE F4 402 METHYL (R)-(+)-3-METHYL GLUTARATE E4404 2,3:4,6-DI-O-ISOPROPYLIDENE-2-KETO-L- D4 405 GULCONIC ACIDD-(−)-QUINIC ACID C4 501 L-ALPHA-HYDROXYISOVALERIC ACID B4 502L-(−)-3-PHENYLLACTIC ACID A4 503 L-MANDELIC ACID H5 505 (R)-4-BROMOMANDELIC ACID G5 506 (R)-4-(3-METHYLPHENYL) MANDELIC ACID F5 507(R)-4-(2-METHYLPHENYL) MANDELIC ACID E5 508 (R)-4-(4-METHYLPHENYL)MANDELIC ACID D5 509 (R)-4-(3-CHLOROPHENYL) MANDELIC ACID C5 510(R)-4-PHENYL MANDELIC ACID B5 511 (S)-4-(3-METHOXYPHENYL) MANDELIC ACIDA5 512 (S)-4-(4-FLUOROPHENYL) MANDELIC ACID H6 513(S)-4-(4-TRIFLUOROMETHYLPHENYL) MANDELIC G6 514 ACIDBICYCLO[2.2.1]-5-HEPTENE-2-CARBOXYLIC ACID F6 601 MONO-METHYLCIS-5-NORBORNENE-ENDO-2,3- E6 603 DICARBOXYLATE (S)-(+)-KETOPINIC ACIDD6 604 (4R)-(−)-2-HYDROXY-5,5-DIMETHYL-4-PHENYL- C6 7011,3,2-DIOXAPHOSPHORINANE 2-OXIDE(S)-(−)-4-(2-CHLOROPHENYL)-2-HYDROXY-5,5- B6 702DIMETHYL-1,3,2-DIOXAPHOSPHORINATE 2-OXIDE(R)-(+)-N-(1-PHENYLETHYL)PHTHALAMIC ACID A6 801 1-METHYL(1S,2R)-(+)-CIS-1,2,3,6-TETRAHYDRO- H7 802 PHTHALATE(S)-(+)-2-(6-MERTHOXY-2-NAPHTHYL)PROPIONIC G7 901 ACID(S)-(+)-2-PHENYLPROPIONIC ACID F7 903(S)-(−)-2-(PHENYLCARBAMOYLOXY)PROPIONIC E7 904 ACID(S)-(−)-2-ACETOXYPROPIONIC ACID D7 905 (R)-(−)-PHENYLSUCCINIC ACID C71001 L-MALIC ACID B7 1002 S-METHYLSUCCINIC ACID A7 1003(+)-DI-P-TOLUYOYL-D-TARTARIC ACID H8 1101 DIBENZOYL-L-TARTARIC ACID G81102 D-TARTARIC ACID F8 1103 TRANS 2-(2-METHOXYPHENYL)-5-OXO E8 1203TETRAHYDROFURAN-3-CARBOXYLIC ACID (S)-(−)-CITRONELLIC ACID D8 1202(R)-(+)-ALPHA-METHOXY-ALPHA- C8 1201 (TRIFLUOROMETHYL)PHENYLACETIC ACID(R)-4-BROMO MANDELIC ACID B8 506

[0103] After removing the plate from the oven, well GI appeared toimmediately furnish a solid. After standing for 1 week wells G1, D1, A2,F3, H4, G4, C4, H5 and D7 appeared to be solid. Submitted formicroscopical examination and if appropriate DSC analysis. Well RefChiral acid Microscopy Outcome C4 501 D-(−) Quinic Acid gum/crystalmixture D1 108 N-Acetylhydroxy-L-proline gum/crystal mixture D7 905(S)-(−)-2-Acetoxypropionic acid gum/crystal mixture F3 201(S)-(+)-2-Methylbutyric acid gum/crystal mixture G1 104BOC-O-Benzyl-L-tyrosine microcrystalline or amorphous G4 401D-Pyroglutamic acid mainly crystalline (some gum) H4 304D-(+)-10-Camphorsulfonic acid gum/crystal mixture H5 505 L-Mandelic acidgum/crystal mixture A2 121 (−)-Cbz-Piperazic acid not analysed

[0104] DSC of sample G1 comprised two overlapping peaks, suggesting thecompound was indeed crystalline and of the eutectic type. The largeoverlap of peaks did not allow sufficient data to be extracted foreutectic point estimation. Qualitatively though the large peak size forthe second peak relative to the first suggested the chiral acid shouldbe a reasonably good resolving agent. Sample G4 also looked like a broadtwo peak melting endothermn, albeit rather broad and noisy. DSCthermograms of the remaining samples were complex and broad or showedonly a single melting endotherm.

[0105] Taking all the data together (DSC, crystallization behaviour, andmicroscopy), N-Boc-O-Benzyl-L-tyrosine was predicted to be a resolvingagent for biarly III (R¹═R²═Et, R³═Ph, R⁶═H).

[0106] Method 2—Salt Formation: II) Resolution:

[0107] A suspension of (±)-biaryl III (R¹═R²═Et, R³═Ph, R⁶═H) 1.000 g(2.840 mmol) and N-Boc-O-Benzyl-L-tyrosine 1.055 g (2.840 mmol) inisopropanol (9.9 ml) was heated at reflux to furnish a clear solution.Heating was removed and the solution allowed to cool naturally withstirring. After reaching room temperature the solution is left to stirfor a further 1 h, then the precipitated solid collected by suction,washing out with the minimum of cold isopropanol (ca 20-30 ml at 5-10°C.). The resulting solid is dried in a vacuum oven at 40° C. overnightto yield the pure salt 0.66 g (32%). NMR of the salt confirmedcrystallization of a 1:1 salt. The diastereomeric excess (de) of thissalt was >90% as evidenced by Chiral HPLC (conditions as above) with thelevorotatory enantiomer of biaryl III being in excess. The mother liquorwas similarly enriched in the dextrorotatory enantiomer. Both fractionscan be processed to give enantiomerically pure biaryl III (>99.9% ee) bycracking the enriched salts back to the parent amine, followed by asingle recrystallization of the parent amine.

[0108]FIG. 1 illustrates a corrrelation graph provided for determinationof the volume of isopropanol required when using salt which is initiallyenriched in one enantiomer. This is useful for instance for obtaininghomochiral (+) enantiomer by crystallisation of enriched liquor materialwith the corresponding D-tyrosine derivative.

EXAMPLE A2 Enantioselective Acylation Using a Catalyst of Formula III

[0109] Catalytic Kinetic Resolution of 1-(1-naphthyl)ethanol (IX,R⁸=1-naphthyl, R⁹═Me)

[0110] To a solution of (±)-1-(1-naphthyl)ethanol (2.20 g, 12.8 mmol),triethylamine (1.3 mL, 9.6 mmol) and catalyst (+)-III (R¹═R²═Et, R³═Ph,R⁶═H) (45 mg, 0.13 mmol) in toluene (25 mL) was added dropwiseisobutyric anhydride (3.2 mL, 19 mmol) at −78° C. The reaction mixturewas stirred at this temperature for 30 h and quenched by slow additionof methanol (10 mL). After additional 15 min at −78° C., the reactionmixture was allowed to warm to room temperature and the solvents wereevaporated in vacuo. The residue was dissolved in dichloromethane andwashed with 1 M K₂CO₃ and brine. The organic layer was concentrated invacuo and the residue purified by flash chromatography (CH₂Cl₂/petroleumether, 1/1→CH₂Cl₂→EtOAc) to give ester (1S)-1-naphthylethyl2-methylpropanoate (1.73 g, 56%) as a pale yellow oil, alcohol(R)-1-(1-naphthyl)cthanol (956 mg, 43%) as a colourless oil, andcatalyst (+)-III (R¹═R²═Et, R³═Ph, R⁶═H) (43 mg, 96%) as a colourlessoil. A small sample of ester (IS)-1-naphthylethyl 2-methylpropanoate washydrolysed with 5%NaOH in MeOH and the resulting alcohol analysed bychiral HPLC (Chiralcel OD; hexanes/2-propanol 90/10, 1 mL min⁻¹, 35° C.)which showed enantiomeric excess of 73.7%. Alcohol(R)-1-(1-naphthyl)ethanol was analysed by the same method and itsenantiomeric excess was shown to be 97.0%. This corresponds toselectivity factor s=26.8 at 56.8% conversion. The recovered catalyst(+)-III (R¹═R²═Et, R³═Ph, R⁶═H) was shown to retain its optical purity(enantiomeric excess >99.9%) by chiral HPLC analysis (Chiralcel OD;hexanes/ethyl acetate/diethylamine 80/19.2/0.8, 1 mL min⁻¹, 20° C.).

EXAMPLES A2-A13

[0111] Catalytic Kinetic Resolutions of Further Secondary Alcohols ofFormula IX.

[0112] The results are shown in Table 1 were obtained using thefollowing representative experimental procedure (Table 1, Exp A7): Asolution of (±)-1-(1-naphthyl)ethanol (172 mg, 1.00 mmol), Et₃N (104 μL,0.75 mmol), and catalyst (−)-III (R¹═R²═Et, R³═Ph, R⁶═H) (3.5 mg, 10μmol) in toluene (2.0 mL) was cooled to −78° C. During vigorousstirring, (¹PrCO)₂O (331 μl, 2.00 mmol) was added dropwise over 3 min.After 2 h at −78° C., ˜1 mL of the reaction mixture was removed rapidlyvia syringe, added to MeOH (2 mL), and stirred at room temperature for15 min. The solvents were then evaporated in vacuo and the alcohol andester were separated by flash chromatography (petroleumether/CH₂Cl₂→CH₂Cl₂). After 504 min, the reminder of the reaction wasquenched by the dropwise addition of MeOH (3 mL) over 2 min. After 15min at −78° C. and 15 min at room temperature, the solvents wereevaporated in vacuo and the alcohol and ester were separated asdescribed above. The esters obtained from the two aliquots werehydrolysed by heating to reflux in 5% NaOH/MeOH (2 mL) for 5 min. Afterevaporation of the solvent, the residue was passed through a short flashsilica column eluted with EtOAc. The enantiomeric excess for theunreacted alcohols and the alcohols obtained by the ester saponificationwas established by analytical chiral HPLC (Chiralcel OD column, 1 cm×25cm; hexanes/2-propanol, 90/10; 1 mL min⁻¹; 30° C.). The results aregiven in Table 1 (Exp A7). TABLE 1 aa = acetic anhydride, iba-isobutyricanhydride Acylating Conversion Selectivity Agent Time Ee Ee C s Exp R⁸R⁹ (equiv) (min) (alcohol) (ester) (%) (%) A2 1-naphthyl Me aa (2.0) 12014.16 77.09 15.52 8.88 504 46.57 69.91 39.98 8.87 A3 1-naphthyl Me aa(0.75) 120 4.87 80.46 5.71 9.69 437 17.53 77.37 18.47 9.30 A4 1-naphthylMe aa (0.75) 120 18.63 69.47 21.15 6.65 379 43.05 63.7 40.33 6.82 A51-naphthyl Me aa (0.75) 120 5.09 79.5 6.02 9.21 456 14.56 77.12 15.888.92 A6 1-naphthyl Me aa (0.75) 120 2.87 74.72 3.70 7.11 617 10.17 72.9512.24 7.06 A7 1-naphthyl Me iba (2.0) 120 18.56 89.33 17.20 21.27 50462.37 83.64 42.72 21.18 A8 Ph Me iba (2.0) 456 49.89 78.13 38.97 13.30A9 Ph Et iba (2.0) 580 43.07 79.15 35.24 13.08 A10 Ph isoPr iba (2.0)606 44.46 66.52 40.06 7.64 A11 Ph tertBu iba (2.0) 631 18.78 88.78 17.4620.21 A12 Ph isoPr iba (2.0) 606 29.8 72.69 29.08 8.43 A13 1-naphthyl Meiba (1.0) 480 26.28 91.38 22.34 28.69

[0113] Further advantages of the invention are apparent from theforegoing.

1. A chiral catalyst as only one of its atropisomers which is enantiomerically enriched such that its ee is greater than or equal to 98%, comprising a 3,4-disubstituted pyridine of formula I

wherein the 3-substituent Z is substantially hindered from rotation about the bond (sp²-sp² biaryl axis) linking it to pyridine, and wherein each of R¹ and R² are independently selected from C₁₋₃₀ alkyl, C₃₋₃₀ cyclo alkyl and/or C₃₋₃₀ aryl, or NR¹ R² form a cyclic amine; wherein R¹ and/or R² may be optionally substituted and/or include one or more heteroatoms.
 2. The catalyst as claimed in claim 1 in the form of its salt, N-functionalised derivative, dimer or oligomer.
 3. Catalyst as claimed in any of claims 1 or 2 wherein the pyridine 5-substituent is hydrogen.
 4. Catalyst as claimed in any of claims 1 to 3 comprising a compound of formula II:

wherein R¹ and R² are as hereinbefore defined; R³ is selected from C₁₋₂₀ alkyl, C₃₋₂₀ cyclo alkyl and/or C₃₋₂₀ aryl, wherein R³ may be optionally substituted and/or include one or more hetero atoms; R⁴ is C₁₋₂₀ alkyl, C₃₋₂₀ cyclo alkyl and/or C₃₋₂₀ aryl or R⁴ and R⁵ together are a C₃₋₂₀ fused cyclic or aromatic group wherein R⁴ or R⁴ and R⁵ together may be optionally substituted or include one or more hetero atoms; and one or more R⁶ are each independently selected from C₁₋₂₀ alkyl and C₃₋₂₀ aryl, optionally substituted and/or including one or more hetero atoms.
 5. Catalyst as claimed in any of claims 1 to 5 wherein each of R¹ and R² independently are selected from: straight or branched chain lower (C₁₋₅) or higher (C₆₋₂₀) alkyl, more preferably methyl, ethyl, propyl, butyl, pentyl or hexyl, heptyl, octyl; or from C₃₋₂₀ cyclo alkyl, preferably C₃-C₁₄ cyclo alkyl; or from C₆₋₂₄ aryl, more preferably an unfused, optionally spiro 1, 2, 3, 4 or 5 ring alkyl or aryl structure; any of which are optionally substituted and/or include at least one heteroatom; or R¹ and R together form an optionally substituted cyclo amine, such as

wherein m=1-8 and each Y is independently selected from (CH₂)_(n)Y′_(p) wherein n 1-8, p=0-4 and the sum of n and p is at least 2, and each Y′ is independently selected from NR⁷, O, S, P or Si wherein R⁷ is as hereinbefore defined for R¹
 6. Catalyst as claimed in claim 5 wherein Y is (CH₂)_(n′)Y′ wherein n′ is 1-3 or the cyclic amine is

or forms a dimer or oligomer of a moiety of compound of formula I:


7. Catalyst as claimed in any of claims 4 to 7 wherein R³ is as defined for R¹ and R² in claim 5, or R³ comprises optionally substituted phenyl or biphenyl, such as optionally substituted (3,5-diphenyl)phenyl, such as [(3′,3″,5′, 5″-tetramethyl)-3,5-diphenyl]phenyl.
 8. Catalyst as claimed in any of claims 1 to 7 comprising a compound of formula III:

wherein R¹-R³ and R⁶ are as hereinbefore defined; or a salt, N-functionalised derivative, dimer or oligomer thereof.
 9. Catalyst as claimed in claim 8 in which: R¹ and R² are methyl, ethyl, propyl, or butyl; or R¹ and R² together form a pyrrolidinyl-, piperidinyl- or morpholinyl ring; and R³ comprises a phenyl, 4′-biphenyl, (3,5-diphenyl)phenyl, or [(3′,3″, 5′, 5″-tetramethyl)-3,5-diphenyl]phenyl.
 10. Catalyst as claimed in any of claims 1 to 9 characterised with respect to the atropisomeric moiety by selection of the group preventing rotation about the pyridine 3-bond, the active catalytic moiety by selection of the amine substituents, and the transformation selective moiety by variation at the pyridine N.
 11. Catalyst as claimed in any of claims 1 to 10 which is a catalyst effective for acylation reactions.
 12. Composition or a support comprising a catalytically effective amount of a catalyst as hereinbefore defined in any of claims 1 to 11 together with suitable solvent, dilutent and the like or together with a suitable linker on a macromolecule, polymer or a solid support.
 13. Compound of formula I, II or III as hereinbefore defined, in any of claims 1 to
 12. 14. Process for the preparation of a compound of formula I, II or III as hereinbefore defined in any of claims 1 to 13 comprising cross-coupling a compound of formula IV with an organometal derivative R³-M (Scheme B).

Wherein each R⁶ independently is hydrogen or is defined as hereinabove, and R¹,R²,R³,R⁴, and R⁵ are defined as hereinabove and wherein X is a group which is such that palladium or nickel or a similar transition metal can be oxidatively inserted into the bond between X and the adjacent aryl carbon atom. M is Li, Mg, Zn, Hg, Ti, Al, Zr, Tl, Sn, B and mixtures thereof or a derivative, salt or “ate” complex thereof.
 15. Process as claimed in claim 14 wherein X is a halide, sulfonate, for example trifloxy (OTf), or diazonium salt.
 16. Process as claimed in claim 14 or 15 in which intermediate IV wherein X═OTf is cross-coupled with an appropriate organo-Grignard derivative (R³-MgBr) in the presence of a catalytic quantity of palladium(0).
 17. Process as claimed in any of claims 14 to 16 comprising incorporating chiral ligands in the coupling procedure and obtaining the product directly as a non-racemic mixture.
 18. Process for separation of a racemic mixture of a catalyst or compound as claimed in any of claims 1 to 12 by chiral stationary phase HPLC or by atropisomer-selective transformation with salt formation, enabling resolution.
 19. Process for the preparation of an intermediate of formula IV as hereinbefore defined comprising: cross-coupling with concomitant hydrodehalogenation, of an intermediate 4-aminopyridine derivative of formula VI to an arylmetal V; and, for compounds wherein X≠Y. subsequent conversion of group Y into group X (Scheme C).

Wherein R¹ and R², and R⁴, R⁵, and R⁶ and M are as hereinbefore defined, W is a halide substituent, and Y is as hitherto defined for X or a substituent of the form OR wherein R is a substituent, known in the art as a protecting group, which allows for conversion to the corresponding compound wherein Y=X to the corresponding compound wherein Y═OH which is readily converted to a substituent hitherto defined as X.
 20. Process as claimed in claim 19 wherein W is a bromide and Y is a substituent of the form OR wherein R is a protecting group which allows for conversion by hydrogenolysis to the corresponding phenol wherein Y═OH [e.g. benzyloxy (OBn), or substituted benzyloxy] and transformation of this phenol to an aryl sulfonate (e.g. triflate) suitable for cross-coupling (e.g. by reaction with an appropriate sulfonic anhydride, -fluoride or -chloride).
 21. Process as claimed in claim 19 or 20 wherein the cross-coupling is catalysed by palladium(0), preferably, M=B(OR)₂ which also effects hydrodehalogenation of the 5-halogen substituent.
 22. Process for stereoselective-reaction of a catalyst of formula I, II, III as hereinbefore defined with an optically inactive substrate to provide one or both enantiomers of a derivative thereof, with simultaneous or subsequent recovery of the catalyst.
 23. Process as claimed in claim 22 which comprises the enantioselective acylation by means of kinetic resolution of e.g. a secondary or tertiary alcohol or primary or secondary amine.
 24. Process as claimed in claim 22 or 23 which comprises the reaction of an alcohol of formula IX, wherein R⁸ and R⁹ are independently selected from C₁ _(⁻) ₅₀ alkyl, C₃₋₅₀ cyclo alkyl or C₃₋₃₀ aryl, with an acylating agent R¹⁰COU, wherein R¹⁰ is optionally substituted C₁ _(⁻) ₁₅ alkyl or C₁ _(⁻) ₁₂ aryl and U is an appropriate leaving group, such as anhydride, under acylating conditions in the presence of a enantiomerically highly enriched catalyst (preferably >90% ee) of formula I, II or III as hereinbefore defined, according to Scheme H.


25. Process as claimed in any of claims 22 to 24 in which Catalytic amounts of 0.001 to 2 mol %, preferably 0.01 to 0.2 mol %, more preferably 0.05 to 0.15 mol % are used.
 26. A pharmaceutical, agrochemical, fragrance, flavouring or constituent of a high-value electrically or optically active polymer obtained by the catalytic stereoselective reaction as claimed in any of claims 23 to
 25. 27. A catalyst, compound, process or reaction product substantially as herein described or illustrated with reference to the description or Examples. 